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The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Hansen, Finja LU ; Kalle, Martina LU ; van der Plas, Mariena LU ; Strömdahl, Ann-Charlotte LU ; Malmsten, Martin LU ; Mörgelin, Matthias LU and Schmidtchen, Artur LU (2015) In Journal of Immunology 194(11). p.5397-5406
Abstract
Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4-and TLR2-induced NF-kappa B activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38 alpha and JNK1/2/3. FACS and... (More)
Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4-and TLR2-induced NF-kappa B activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38 alpha and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-kappa B activity and proinflammatory cytokine production in monocytes and macrophages. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
194
issue
11
pages
5397 - 5406
publisher
American Association of Immunologists
external identifiers
  • wos:000354905300040
  • scopus:84929629727
  • pmid:25911750
ISSN
1550-6606
DOI
10.4049/jimmunol.1403009
project
Host-pathogen interactions and the development of chronic infections
language
English
LU publication?
yes
id
a55f88f8-023c-48d8-baa9-ecbcd99190cc (old id 7411571)
date added to LUP
2016-04-01 14:23:39
date last changed
2022-04-14 17:38:48
@article{a55f88f8-023c-48d8-baa9-ecbcd99190cc,
  abstract     = {{Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4-and TLR2-induced NF-kappa B activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38 alpha and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-kappa B activity and proinflammatory cytokine production in monocytes and macrophages.}},
  author       = {{Hansen, Finja and Kalle, Martina and van der Plas, Mariena and Strömdahl, Ann-Charlotte and Malmsten, Martin and Mörgelin, Matthias and Schmidtchen, Artur}},
  issn         = {{1550-6606}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{5397--5406}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of Immunology}},
  title        = {{The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1403009}},
  doi          = {{10.4049/jimmunol.1403009}},
  volume       = {{194}},
  year         = {{2015}},
}